Real-World Data Highlight Value of NOTCH1 Screening in CLL

Chronic lymphocytic leukemia (CLL) remains one of the most common hematologic malignancies, and treatment decisions increasingly depend on molecular features. While TP53 and IGHV mutational status are established predictors guiding therapy, the role of NOTCH1 mutations has been less clearly defined. A bicentric retrospective analysis from 2 French tertiary care centers, published in eJHaem, now suggests that NOTCH1 mutations may serve as an important biomarker for selecting Bruton tyrosine kinase inhibitors (BTKi) therapy.1

The findings highlight the potential value of incorporating NOTCH1 mutation testing into routine decision-making alongside TP53 and IGHV status. | Image credit: Connect world - stock.adobe.com

NOTCH1 is one of the most frequently mutated genes in CLL, present in approximately 20% of newly diagnosed cases and historically associated with poor outcomes in trials using chemotherapy.2 However, it has not been incorporated into current treatment guidelines, unlike TP53 or IGHV, largely because of inconsistent data on its predictive value. With the widespread use of next-generation sequencing (NGS) in CLL, clarifying the prognostic role of NOTCH1 has become increasingly relevant, particularly in the era of targeted therapies.1

The current analysis included 174 patients with CLL diagnosed between 2013 and 2022 who underwent next-generation sequencing prior to the initiation of first-line treatment. NOTCH1 mutations were present in 25.9% of patients at baseline, most commonly a c.7541_7542 deletion in exon 34, accounting for 64.4% of mutations. These alterations were strongly associated with age over 65 years (P = .007) and unmutated IGHV status (P = .002), but showed no correlation with gender, Binet stage, complex karyotype, or TP53 mutation. The median time from diagnosis to first treatment was shorter for patients with mutated NOTCH1 (21.75 months) compared with those without NOTCH1 mutations (45.9 months; P = .06).

Among the 45 patients harboring NOTCH1 mutations, the first-line therapies included immunochemotherapy (n = 15), BTK inhibitors (n = 18), venetoclax-based combinations (n = 2), and other regimens. Outcomes revealed a significant advantage in progression-free survival (PFS) for patients with NOTCH1 mutations treated with BTK inhibitors. Those receiving BTKis didn't reach median PFS at the time of analysis, compared with a median of 50.6 months for those receiving immunochemotherapy (P = .005).

In the subgroup receiving BTKi as first-line therapy, the estimated 2-year PFS was 94% for patients with NOTCH1 mutations, compared to 84% for those without mutations, although this difference was not statistically significant (P = .12). Overall survival (OS) did not differ significantly between therapies (P = .22), suggesting that while BTKis extend durable disease control, longer follow-up will be necessary to clarify their effect on survival outcomes.

Among patients without NOTCH1 mutations, PFS outcomes were similar between the BTKi and immunochemotherapy arms (P = .51). Similarly, within the immunochemotherapy only cohort, NOTCH1 status had no significant impact on PFS (P = .14). These findings contrast with prior trials using chemotherapy, such as CLL4, which identified NOTCH1 mutation as an independent predictor of inferior PFS and OS.3 The authors note, "our study was not designed to compare NOTCH1-mutated and unmutated patients, this result may be related to a lack of power."

Historical clinical trials, such as the randomized RESONATE trial, indicated that NOTCH1 mutations were associated with shorter PFS following ofatumumab treatment, but not with ibrutinib, supporting the current study's rationale that BTK inhibitors may neutralize the adverse prognostic impact of NOTCH1 mutations.4

While OS benefit has not yet been demonstrated, the marked improvement in PFS is clinically relevant for treatment planning.1 In clinical practice, these findings highlight the potential value of incorporating NOTCH1 mutation testing into routine decision-making alongside TP53 and IGHV status. Screening could help identify patients most likely to benefit from BTKi therapy, particularly older individuals or those with unmutated IGHV. Although the study did not evaluate combination regimens, the authors noted that "The impact of NOTCH1 mutations on combination therapies, such as obinutuzumab-venetoclax or venetoclax-BTKi, is yet to be determined."

References

1. Haméon C, Houot R, Gyan E, et al. NOTCH1 mutation is associated with response to bruton tyrosine kinase Iinhibitors in chronic lymphocytic leukemia: a retrospective study. EJHaem. 2025;6(5):e70146. doi:10.1002/jha2.70146
2. Rossi D, Rasi S, Fabbri G, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. 2012;119(2):521-9. doi:10.1182/blood-2011-09-379966
3. Oscier DG, Rose-Zerilli MJ, Winkelmann N, et al. The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood. 2013;121(3):468-75. doi:10.1182/blood-2012-05-429282
4. Brown JR, Hillmen P, O'Brien S, et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018;32(1):83-91. doi:10.1038/leu.2017.175